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题名:Glitazones exert multiple effects on beta-cell stimulus-secretion coupling.
作者:DUFER M; NOACK K; EDALAT A; KRIPPEIT-DREWS P; DREWS G;
来源:Mol Pharmacol. 2013 Jan;83(1):51-60. doi: 10.1124/mol.112.081638. Epub 2012 Sep [ IF= 0.00 ] ]
URL :10.1124/mol.112.081638
日期:20130131
摘要:Earlier studies suggest that glitazones exert beneficial effects in patients with
type 2 diabetes by directly affecting insulin secretion of beta-cells, besides
improving the effectiveness of insulin in peripheral tissues. The effects of
glitazones on stimulus-secretion coupling (SSC) are poorly understood. We tested
the influence of troglitazone and pioglitazone on different parameters of SSC,
including insulin secretion (radioimmunoassay), cell membrane potential, various
ion currents (patch-clamp), mitochondrial membrane potential (DeltaPsi), and
cytosolic Ca(2+) concentration (fluorescence). Troglitazone exerted stimulatory,
inhibitory, or no effects on insulin secretion depending on the drug and glucose
concentration. It depolarized the DeltaPsi, thus lowering ATP production, which
resulted in opening of ATP-dependent K(+) channels (K(ATP) channels) and reduced
insulin secretion. However, it also exerted direct inhibitory effects on K(ATP)
channels that can explain enhanced insulin secretion. Troglitazone also inhibited
the currents through voltage-dependent Ca(2+) and K(+) channels. Pioglitazone was
less effective than troglitazone on all parameters tested. The effects of both
glitazones were markedly reduced in the presence of bovine serum albumin.
Glitazones exert multiple actions on beta-cell SSC that have to be considered as
undesired side effects because the influence of these compounds on beta-cells is
not controllable. The final effect on insulin secretion depends on many
parameters, including the actual glucose and drug concentration, protein binding
of the drug, and the drug by itself. Troglitazone and pioglitazone differ in
their influence on SSC. It can be assumed that the effects of pioglitazone on
beta-cells are negligible under in vivo conditions.

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